Regulation of the Aurora-A gene following topoisomerase I inhibition: implication of the Myc transcription Factor
| Autor: | Erick Gamelin, Benjamin Barré, Claude Prigent, Arnaud Vigneron, Sandrine Giraud, Julia Cherier, Isabelle Valo, Sandy Courapied, Marie-Bérangère Troadec, Olivier Coqueret |
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| Přispěvatelé: | BMC, Ed., Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), Département de pathologie biologique, CRLCC Paul Papin, This work was supported by a fellowship (to A.V and S.C) and a grant from Institut National du Cancer and from the Ligue contre le Cancer (Equipes labélisées 2007 to O.C, C.P and E.G), a grant from Canceropole Grand Ouest (O.C, C.P and E.G.) and a fellowship from INSERM-Region and Rotary (to J.C)., Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
MESH: DNA Primers
Cancer Research Chromatin Immunoprecipitation MESH: Cell Line Tumor [SDV.CAN]Life Sciences [q-bio]/Cancer Topoisomerase-I Inhibitor MESH: Base Sequence Protein Serine-Threonine Kinases lcsh:RC254-282 MESH: Protein-Serine-Threonine Kinases Gene Expression Regulation Enzymologic Proto-Oncogene Proteins c-myc 03 medical and health sciences 0302 clinical medicine [SDV.CAN] Life Sciences [q-bio]/Cancer Aurora Kinases [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Cell Line Tumor MESH: Promoter Regions Genetic MESH: Proto-Oncogene Proteins c-myc Humans Promoter Regions Genetic Mitosis 030304 developmental biology DNA Primers MESH: Chromatin Immunoprecipitation 0303 health sciences MESH: Humans biology Base Sequence Topoisomerase MESH: Gene Expression Regulation Enzymologic Research Cell cycle G2-M DNA damage checkpoint lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Oncology DNA Topoisomerases Type I Centrosome 030220 oncology & carcinogenesis Cancer research biology.protein [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Molecular Medicine Centrosome separation Chromatin immunoprecipitation MESH: DNA Topoisomerases Type I |
| Zdroj: | Molecular Cancer Molecular Cancer, Vol 9, Iss 1, p 205 (2010) Molecular Cancer, 2010, 9 (1), pp.205. ⟨10.1186/1476-4598-9-205⟩ Molecular Cancer, BioMed Central, 2010, 9 (1), pp.205. ⟨10.1186/1476-4598-9-205⟩ |
| ISSN: | 1476-4598 |
| DOI: | 10.1186/1476-4598-9-205⟩ |
| Popis: | During the G2 phase of the cell cycle, the Aurora-A kinase plays an important role in centrosome maturation and progression to mitosis. In this study, we show in colorectal cell lines that Aurora-A expression is downregulated in response to topoisomerase I inhibition. Using chromatin immunoprecipitation assays, we have observed that the Myc transcription factor and its Max binding partner are associated with the Aurora-A promoter during the G2 phase of the cell cycle. RNA interference experiments indicated that Myc is involved in the regulation of the Aurora-A gene. Following topoisomerase I inhibition, the expression of Myc decreased whereas Mad was upregulated, and the association of Myc and Max with the promoter of the kinase was inhibited. In parallel, an increased association of Mad and Miz-1 was detected on DNA, associated with an inhibition of the recruitment of transcriptional coactivators. Interestingly, a gain of H3K9 trimethylation and HP1γ recruitment was observed on the Aurora-A promoter following sn38 treatment, suggesting that this promoter is located within SAHF foci following genotoxic treatment. Since Aurora-A is involved in centrosome maturation, we observed as expected that topoisomerase I inhibition prevented centrosome separation but did not affect their duplication. As a consequence, this led to G2 arrest and senescence induction. These results suggest a model by which the Aurora-A gene is inactivated by the G2 checkpoint following topoisomerase I inhibition. We therefore propose the hypothesis that the coordinated overexpression of Myc and Aurora-A, together with a downregulation of Mad and Miz-1 should be tested as a prognosis signature of poor responses to topoisomerase I inhibitors. |
| Databáze: | OpenAIRE |
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